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The
journal of medicine
established in 1812 October 19, 2017 vol. 377 no. 16

Dual Antithrombotic Therapy with Dabigatran after PCI


in Atrial Fibrillation
ChristopherP. Cannon, M.D., DeepakL. Bhatt, M.D., M.P.H., Jonas Oldgren, M.D., Ph.D., GregoryY.H. Lip, M.D.,
StephenG. Ellis, M.D., Takeshi Kimura, M.D., Michael Maeng, M.D., Ph.D., Bela Merkely, M.D.,
Uwe Zeymer, M.D., Savion Gropper, M.D., Ph.D., Matias Nordaby, M.D., Eva Kleine, M.Sc., Ruth Harper, Ph.D.,
Jenny Manassie, B.Med.Sc., JamesL. Januzzi, M.D., JurrienM. tenBerg, M.D., Ph.D., P.Gabriel Steg, M.D.,
and StefanH. Hohnloser, M.D., for the RE-DUAL PCI Steering Committee and Investigators*

a bs t r ac t

BACKGROUND
Triple antithrombotic therapy with warfarin plus two antiplatelet agents is the standard of The authors affiliations are listed in the
care after percutaneous coronary intervention (PCI) for patients with atrial fibrillation, but Appendix. Address reprint requests to
Dr. Cannon at the Baim Institute for Clini-
this therapy is associated with a high risk of bleeding. cal Research, 930 Commonwealth Ave.,
METHODS Boston, MA, 02215 or at christopher
.cannon@baiminstitute.org.
In this multicenter trial, we randomly assigned 2725 patients with atrial fibrillation who had
undergone PCI to triple therapy with warfarin plus a P2Y12 inhibitor (clopidogrel or ticagrelor) * A complete list of investigators in the
Randomized Evaluation of Dual Anti-
and aspirin (for 1 to 3 months) (triple-therapy group) or dual therapy with dabigatran (110 mg thrombotic Therapy with Dabigatran ver-
or 150 mg twice daily) plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and no aspirin (110-mg sus Triple Therapy with Warfarin in Pa-
and 150-mg dual-therapy groups). Outside the United States, elderly patients (80 years of age; tients with Nonvalvular Atrial Fibrillation
Undergoing Percutaneous Coronary In-
70 years of age in Japan) were randomly assigned to the 110-mg dual-therapy group or the tervention (RE-DUAL PCI) trial is pro-
triple-therapy group. The primary end point was a major or clinically relevant nonmajor bleed- vided in the Supplementary Appendix,
ing event during follow-up (mean follow-up, 14 months). The trial also tested for the noninfe- available with the full text of this article
at NEJM.org.
riority of dual therapy with dabigatran (both doses combined) to triple therapy with warfarin
with respect to the incidence of a composite efficacy end point of thromboembolic events This article was published on August 27,
2017, at NEJM.org.
(myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization.
RESULTS N Engl J Med 2017;377:1513-24.
DOI: 10.1056/NEJMoa1708454
The incidence of the primary end point was 15.4% in the 110-mg dual-therapy group as Copyright 2017 Massachusetts Medical Society.
compared with 26.9% in the triple-therapy group (hazard ratio, 0.52; 95% confidence inter-
val [CI], 0.42 to 0.63; P<0.001 for noninferiority; P<0.001 for superiority) and 20.2% in the
150-mg dual-therapy group as compared with 25.7% in the corresponding triple-therapy
group, which did not include elderly patients outside the United States (hazard ratio, 0.72;
95% CI, 0.58 to 0.88; P<0.001 for noninferiority). The incidence of the composite efficacy end
point was 13.7% in the two dual-therapy groups combined as compared with 13.4% in the
triple-therapy group (hazard ratio, 1.04; 95% CI, 0.84 to 1.29; P=0.005 for noninferiority).
The rate of serious adverse events did not differ significantly among the groups.
CONCLUSIONS
Among patients with atrial fibrillation who had undergone PCI, the risk of bleeding was
lower among those who received dual therapy with dabigatran and a P2Y12 inhibitor than
among those who received triple therapy with warfarin, a P2Y12 inhibitor, and aspirin. Dual
therapy was noninferior to triple therapy with respect to the risk of thromboembolic events.
(Funded by Boehringer Ingelheim; RE-DUAL PCI ClinicalTrials.gov number, NCT02164864.)

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The n e w e ng l a n d j o u r na l of m e dic i n e

I
n determining the best approach for farin among patients with atrial fibrillation who
antithrombotic therapy in patients with atrial had undergone PCI.
fibrillation who are undergoing percutane-
ous coronary intervention (PCI), it can be diffi- Me thods
cult to balance the prevention of thrombosis
A Quick Take is
available at with the risk of bleeding.1,2 Oral anticoagulation Trial Oversight
NEJM.org is indicated in patients with atrial fibrillation for The trial was designed and led by an executive
the prevention of stroke and systemic embolism, steering committee and the sponsor (Boehringer
whereas dual antiplatelet therapy with a P2Y12 Ingelheim) in collaboration with an international
inhibitor plus aspirin is indicated in patients who steering committee (for a complete list of com-
are undergoing PCI with stent implantation for mittee members, see the Supplementary Appen-
the prevention of cardiovascular events, including dix, available with the full text of this article at
stent thrombosis.3-5 Until recently, most guide- NEJM.org). The protocol and amendments (avail-
lines recommended both anticoagulation and able at NEJM.org) were approved by the ethics
dual antiplatelet therapy (triple therapy).3,6-9 How- committee at each participating center. Data were
ever, studies have shown that these regimens are reviewed regularly throughout the trial by an
associated with high rates of major bleeding, independent data and safety monitoring com-
and such findings have prompted efforts to seek mittee. The trial had an open-label design; how-
new therapeutic strategies.10-15 ever, all primary and secondary end-point events
Two new promising approaches have emerged were adjudicated by an independent committee
to reduce the risk of bleeding among patients in whose members were unaware of the treatment
whom both oral anticoagulation and antiplatelet assignments. The authors vouch for the accuracy
therapy are indicated. The first approach is the and completeness of the data and analyses and
use of nonvitamin K antagonist oral anticoagu- the adherence of the trial to the protocol. The
lants, the first of which was the oral direct first draft of the manuscript was written by the
thrombin inhibitor dabigatran. Two doses of first author and revised in collaboration with all
this agent were each shown to be effective for the authors. Assistance with editing of the
stroke prevention among patients with atrial fi- manuscript before submission was provided by a
brillation, including those receiving either single medical writer funded by Boehringer Ingelheim.
or dual antiplatelet therapy.16,17 The second ap- All the authors made the decision to submit the
proach is the omission of aspirin from the stan- manuscript for publication. Boehringer Ingelheim
dard regimen and the use of a single P2Y12 inhibi- provided dabigatran and warfarin, served as the
tor in combination with an oral anticoagulant. data coordinating center, performed site moni-
In a moderate-sized trial involving patients who toring, and performed the statistical analysis
were undergoing PCI and in whom anticoagula- (which was reviewed by the executive steering
tion was indicated, the risk of bleeding (and committee).
vascular events) was lower with this dual-therapy
approach than with standard triple therapy.18 Patient Population
Data from another trial supported the use of Men and women who were at least 18 years of
triple therapy for a shortened duration.19 Most age were eligible for inclusion in the trial if they
recently, another trial showed that the risk of had nonvalvular atrial fibrillation and had suc-
bleeding was lower with a regimen of reduced- cessfully undergone PCI with a bare-metal or
dose rivaroxaban plus a P2Y12 inhibitor than with drug-eluting stent within the previous 120 hours.23
standard triple therapy.20-22 We conducted the Nonvalvular atrial fibrillation could be paroxys-
RE-DUAL PCI trial (Randomized Evaluation of mal, persistent, or permanent, but it could not
Dual Antithrombotic Therapy with Dabigatran be secondary to a reversible disorder unless
versus Triple Therapy with Warfarin in Patients long-term treatment with an oral anticoagulant
with Nonvalvular Atrial Fibrillation Undergoing was anticipated. Patients who had been receiving
Percutaneous Coronary Intervention) to compare treatment with an oral anticoagulant before PCI
the use of two regimens of dual antithrombotic and those who had not received oral anticoagu-
therapy that included dabigatran with the use of lation were eligible. The indication for PCI could
triple antithrombotic therapy that included war- be either an acute coronary syndrome or stable

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Dual Antithrombotic Ther apy with Dabigatr an

coronary-artery disease. Key exclusion criteria when the trial anticoagulant (dabigatran or war-
were the presence of bioprosthetic or mechanical farin) was discontinued; a follow-up visit took
heart valves, severe renal insufficiency (creatinine place 4 weeks thereafter. The trial continued until
clearance, <30 ml per minute), or other major all the patients had a minimum of 6 months of
coexisting conditions. A complete list of inclusion follow-up and the target number of end-point
and exclusion criteria is provided in Table S1 in events was anticipated to be reached.
the Supplementary Appendix. Written informed
consent was obtained from all the patients. End Points
The primary end point was the first major or
Treatments clinically relevant nonmajor bleeding event, as
Patients had received standard antithrombotic defined by the International Society on Throm-
treatment for the PCI procedure. After PCI, pa- bosis and Hemostasis (ISTH; detailed definitions
tients who were eligible for enrollment in the are provided in Table S2 in the Supplementary
trial were randomly assigned to receive one of Appendix), in a time-to-event analysis.24 A main
three treatments: dual therapy with dabigatran secondary end point was a composite efficacy
etexilate (110 mg twice daily) plus either clopi- end point of thromboembolic events (myocardial
dogrel or ticagrelor (110-mg dual-therapy group), infarction, stroke, or systemic embolism), death,
dual therapy with dabigatran etexilate (150 mg or unplanned revascularization (PCI or coronary-
twice daily) plus either clopidogrel or ticagrelor artery bypass grafting). Other secondary end
(150-mg dual-therapy group), or triple therapy points included a combined end point of throm-
with warfarin plus aspirin (100 mg daily) and boembolic events or death, as well as the indi-
either clopidogrel or ticagrelor (triple-therapy vidual thromboembolic events and definite stent
group). In the triple-therapy group, aspirin was thrombosis. For detailed definitions of the end
discontinued after 1 month in patients in whom a points and a list of other safety end points, see
bare-metal stent was implanted and after 3 months Tables S3 and S4 in the Supplementary Appendix.
in patients in whom a drug-eluting stent was im- All clinical end-point events were adjudicated by
planted (Fig. S1 in the Supplementary Appendix). an independent committee whose members were
Randomization was performed with the use unaware of the treatment assignments. Subgroup
of permuted blocks, with stratification accord- analyses were planned across major subgroups.
ing to age group (nonelderly or elderly [<80 or
80 years of age; <70 or 70 years of age in Statistical Analysis
Japan]) and region (United States, Japan, or other The trial was designed to test the two safety
countries). All patients in the United States and hypotheses that dual therapy with dabigatran at
nonelderly patients in other countries were ran- a dose of 110 mg twice daily and dual therapy
domly assigned to the 110-mg dual-therapy group, with dabigatran at a dose of 150 mg twice daily
the 150-mg dual-therapy group, or the triple- would be noninferior to triple therapy with war-
therapy group in a 1:1:1 ratio. Elderly patients farin with respect to the primary end point. A
outside the United States were randomly assigned noninferiority margin of 1.38 for the upper
to the 110-mg dual-therapy group or the triple- boundary of the 95% confidence interval was
therapy group in a 1:1 ratio; they were not eli- used by the Food and Drug Administration for
gible to be assigned to the 150-mg dual-therapy registration trials of nonvitamin K antagonist
group, in accordance with the recommendations anticoagulants to evaluate the risk of stroke or
of the dabigatran label in those countries (Fig. 1). systemic embolism.25 The same noninferiority
All the patients were to receive either clopido- margin was used to evaluate the risk of bleeding
grel (75 mg daily) or ticagrelor (90 mg twice and thromboembolic events in this trial, because
daily) for at least 12 months after randomiza- it was considered to be the most clinically rele-
tion; the choice of agent was at the discretion of vant available reference in the absence of any
the investigator. The dose of warfarin was ad- other type of data.23 The incidence of the pri-
justed to ensure that the patients international mary end point was compared between the 110-mg
normalized ratio (INR) was within a range of 2.0 dual-therapy group and the triple-therapy group
to 3.0. Follow-up was performed every 3 months. with the use of a stratified Cox proportional-
All the patients had an end-of-treatment visit hazards regression model, with stratification ac-

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The n e w e ng l a n d j o u r na l of m e dic i n e

A Enrollment, Randomization, and Treatment

2845 Patients were assessed for eligibility

2725 Underwent randomization

981 Were assigned to receive dual therapy 763 Were assigned to receive dual therapy 981 Were assigned to receive triple
with dabigatran at a dose of 110 mg with dabigatran at a dose of 150 mg therapy with warfarin

95 Discontinued participation 60 Discontinued participation 132 Discontinued participation


in the trial prematurely in the trial prematurely in the trial prematurely
65 Had an adverse event 41 Had an adverse event 59 Had an adverse event
2 Had a protocol violation 4 Had a protocol violation 1 Had a protocol violation
4 Were lost to follow-up 3 Were lost to follow-up 2 Were lost to follow-up
21 Withdrew consent 8 Withdrew consent 56 Withdrew consent
3 Had other reason 4 Had other reason 14 Had other reason
22 Had no data on vital 6 Had no data on vital 40 Had no data on vital
status because they status because they status because they
were lost to follow-up or were lost to follow-up or were lost to follow-up
withdrew consent withdrew consent or withdrew consent

972 Received 1 dose of assigned treatment 758 Received 1 dose of assigned treatment 948 Received 1 dose of assigned treatment

B Treatment Groups
54 Were nonelderly patients in the United States
769 Were assigned to receive dual therapy
702 Were nonelderly patients outside the United States
with dabigatran at a dose of 110 mg
13 Were elderly patients in the United States

All patients in the United States 53 Were nonelderly patients in the United States
763 Were assigned to receive dual therapy
and nonelderly patients outside 702 Were nonelderly patients outside the United States
with dabigatran at a dose of 150 mg
the United States 8 Were elderly patients in the United States

61 Were nonelderly patients in the United States


766 Were assigned to receive triple
695 Were nonelderly patients outside the United States
therapy with warfarin
10 Were elderly patients in the United States

212 Were assigned to receive dual therapy


with dabigatran at a dose of 110 mg
Elderly patients outside
the United States
215 Were assigned to receive triple
therapy with warfarin

Figure 1. Enrollment, Randomization, and Treatment.


Shown is the distribution of patients during enrollment, randomization, and treatment (Panel A) and within the treatment groups ac-
cording to country and age group (Panel B). Elderly was defined as 80 years of age or older (70 years of age in Japan), and nonelderly
younger than 80 years of age (<70 years of age in Japan). Elderly patients outside the United States were not eligible to be assigned to
the 150-mg dual-therapy group, in accordance with the recommendations of the dabigatran label in those countries.

cording to age group (nonelderly or elderly [<80 between the 150-mg dual-therapy group and the
or 80 years of age; <70 or 70 years of age in triple-therapy group with the use of an unstrati-
Japan]) (see the Supplementary Appendix). The fied Cox proportional-hazards model. For com-
incidence of the primary end point was compared parisons between the 150-mg dual-therapy group

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Dual Antithrombotic Ther apy with Dabigatr an

and the triple-therapy group, we used a corre- follow-up and had no data on vital status. A total
sponding triple-therapy group that included only of 2.0% of the patients in the 110-mg dual-
patients who had been eligible to be assigned to therapy group, 0.5% in the 150-mg dual-therapy
the 150-mg dual-therapy group (i.e., did not in- group, and 3.9% in the triple-therapy group with-
clude elderly patients outside the United States). drew consent and had no data on vital status at
Therefore, the sample sizes for the 150-mg dual- the end of the trial. Details regarding the times
therapy group and the corresponding triple-ther- at which patients withdrew consent are shown in
apy group are smaller than those for the 110-mg Table S6 in the Supplementary Appendix. Of the
dual-therapy group and the complete triple-therapy patients in each treatment group who completed
group (Fig. 1). The primary analysis, which was the trial, 130 (13.3%) in the 110-mg dual-therapy
performed on an intention-to-treat basis, included group, 99 (13.0%) in the 150-mg dual-therapy
all patients who underwent randomization, regard- group, and 163 (16.6%) in the triple-therapy group
less of whether they received treatment. A sensi- stopped receiving the trial anticoagulant pre-
tivity analysis, which was performed on an on- maturely. The mean duration of treatment with
treatment basis, included all patients who had the trial anticoagulant was 12.3 months, and the
received at least one dose of the trial antico mean duration of follow-up was 14.0 months.
agulant; data on events that occurred more than Baseline characteristics of the patients are
7 days after the trial anticoagulant was perma- shown in Table1 and in Table S7 in the Supple-
nently discontinued were censored. mentary Appendix. The mean age was 70.8 years
Assuming an event rate for the primary end (16.8% of the patients were in the elderly age
point of 14% in each treatment group, we calcu- group), and the index indication for PCI was an
lated that 167 patients with events per group acute coronary syndrome in 50.5% of the patients.
would give the trial 83.6% power to detect the Drug-eluting stents alone were used in 82.6% of
noninferiority of dual therapy with dabigatran to the patients. Most of the patients received clopido-
triple therapy with warfarin, at a one-sided alpha grel; only 12.0% received ticagrelor. Details regard-
level of 0.025. This calculation yielded an esti- ing the use of concomitant antiplatelet therapies
mated total sample size of at least 2500 patients. over time are shown in Table S8 in the Supplemen-
To control the type I error rate, a hierarchical tary Appendix. In the triple-therapy group, the
procedure for multiple testing was used to test mean percentage of time in the therapeutic INR
the major trial hypotheses. For further details, range (calculated by means of the method of
see Table S5 in the Supplementary Appendix. Rosendaal et al.26) was 64%.
In the initial protocol, a sample size of 8520
patients had been planned to allow for a copri- Primary End Point
mary end-point comparison of thromboembolic- The incidence of the primary end point (the first
event rates in each dual-therapy group versus the major or clinically relevant nonmajor bleeding
triple-therapy group; however, enrollment of this event) was 15.4% in the 110-mg dual-therapy
number of patients in a timely fashion was deter- group as compared with 26.9% in the triple-
mined to be infeasible. The protocol was amended therapy group (hazard ratio, 0.52; 95% confidence
to specify the current sample size, and the com- interval [CI], 0.42 to 0.63; P<0.001 for noninferi-
parison of thromboembolic-event rates in the two ority; P<0.001 for superiority) and 20.2% in the
dual-therapy groups combined versus the triple- 150-mg dual-therapy group as compared with
therapy group was changed to a secondary end 25.7% in the corresponding triple-therapy group
point. (hazard ratio, 0.72; 95% CI, 0.58 to 0.88; P<0.001
for noninferiority) (Fig. 2A and 2B and Table2).
Results of the intention-to-treat analysis were
R e sult s
consistent with results of the on-treatment analy-
Participants sis and with results across major subgroups
Between July 21, 2014, and October 31, 2016, a (Table S9 and Fig. S2 in the Supplementary Ap-
total of 2725 patients underwent randomization pendix). The rates of major bleeding alone and
at 414 sites in 41 countries (for a complete list of of total bleeding were significantly lower in both
countries, see the Supplementary Appendix). De- dual-therapy groups than in the triple-therapy
tails regarding patient disposition are shown in group (Table2). In addition, when major bleed-
Figure 1. Only 6 patients (0.2%) were lost to ing was defined according to Thrombolysis in

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Table 1. Baseline Characteristics of the Patients.*

Dual Therapy Dual Therapy Corresponding


with Dabigatran, Triple Therapy with Dabigatran, Triple Therapy
110 mg with Warfarin 150 mg with Warfarin
Characteristic (N=981) (N=981) (N=763) (N=764)
Age yr 71.58.9 71.78.9 68.67.7 68.87.7
Elderly age group no. (%) 225 (22.9) 225 (22.9) 8 (1.0) 8 (1.0)
Male sex no. (%) 728 (74.2) 750 (76.5) 592 (77.6) 594 (77.7)
Diabetes mellitus no./total no. (%) 362/981 (36.9) 371/980 (37.9) 260/763 (34.1) 303/763 (39.7)
Previous stroke no./total no. (%) 74/981 (7.5) 100/980 (10.2) 52/763 (6.8) 77/763 (10.1)
CHA2DS2-VASc score 3.71.6 3.81.5 3.31.5 3.61.5
HAS-BLED score 2.70.7 2.80.8 2.60.7 2.70.8
Creatinine clearance ml/min 76.328.9 75.429.1 83.731.0 81.329.6
Previous myocardial infarction no. (%) 237 (24.2) 268 (27.3) 194 (25.4) 211 (27.6)
Previous PCI no./total no. (%) 326/981 (33.2) 347/980 (35.4) 239/763 (31.3) 272/763 (35.6)
Previous CABG no./total no. (%) 97/981 (9.9) 111/980 (11.3) 79/763 (10.4) 87/763 (11.4)
Type of atrial fibrillation no./total no (%)
Persistent 174/981 (17.7) 178/980 (18.2) 132/763 (17.3) 149/763 (19.5)
Permanent 320/981 (32.6) 318/980 (32.4) 250/763 (32.8) 238/763 (31.2)
Paroxysmal 487/981 (49.6) 484/980 (49.4) 380/763 (49.8) 376/763 (49.3)
Indication for PCI no. (%)
Stable angina or positive stress test 433 (44.1) 429 (43.7) 320 (41.9) 339 (44.4)
Acute coronary syndrome 509 (51.9) 475 (48.4) 391 (51.2) 369 (48.3)
Staged procedure 156 (15.9) 168 (17.1) 138 (18.1) 134 (17.5)
Other 43 (4.4) 62 (6.3) 65 (8.5) 50 (6.5)
Type of stent no./total no. (%)
Drug-eluting 804/979 (82.1) 826/976 (84.6) 621/762 (81.5) 638/759 (84.1)
Bare-metal 148/979 (15.1) 133/976 (13.6) 123/762 (16.1) 107/759 (14.1)
Drug-eluting and bare-metal 19/979 (1.9) 12/976 (1.2) 10/762 (1.3) 9/759 (1.2)
Other 8/979 (0.8) 5/976 (0.5) 8/762 (1.0) 5/759 (0.7)

* Plusminus values are means SD. CABG denotes coronary-artery bypass grafting, and PCI percutaneous coronary intervention.
The corresponding triple-therapy group included only patients who had been eligible to be assigned to the 150-mg dual-therapy group (i.e.,
did not include elderly patients outside the United States).
Elderly was defined as 80 years of age or older (70 years of age in Japan). Stratification according to age group was performed with the use
of an interactive voice-response system.
The CHA2DS2-VASc score reflects the risk of stroke, with values ranging from 0 to 9 and higher scores indicating greater risk.
The HAS-BLED score reflects the risk of major bleeding among patients with atrial fibrillation who are receiving anticoagulant therapy, with
values ranging from 0 to 9 and with higher scores indicating greater risk.
Creatinine clearance was calculated with the use of the CockcroftGault equation. Data are missing for 91 patients in the 110-mg dual-therapy
group, 80 in the triple-therapy group, 61 in the 150-mg dual-therapy group, and 63 in the corresponding triple-therapy group.

Myocardial Infarction (TIMI) criteria, the rate was corresponding triple-therapy group (hazard ra-
lower in both dual-therapy groups than in the tri- tio, 0.51; 95% CI, 0.28 to 0.93; P=0.03) (Table2).
ple-therapy group: 1.4% in the 110-mg dual-thera- Intracranial hemorrhage was rare, but it also oc-
py group as compared with 3.8% in the triple- curred at a lower rate in the 110-mg dual-therapy
therapy group (hazard ratio, 0.37; 95% CI, 0.20 group than in the triple-therapy group (0.3% vs.
to 0.68; P=0.002) and 2.1% in the 150-mg dual- 1.0%; hazard ratio, 0.30; 95% CI, 0.08 to 1.07;
therapy group as compared with 3.9% in the P=0.06) and at a lower rate in the 150-mg dual-

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Dual Antithrombotic Ther apy with Dabigatr an

Figure 2. Primary End Point and Secondary Efficacy A Primary End Point in Dual-Therapy Group (110 mg) vs. Triple-Therapy Group
End Point. 100 Hazard ratio, 0.52 (95% CI, 0.420.63)
Shown is the cumulative incidence of the primary end 90 P<0.001 for noninferiority

Cumulative Incidence
point of major or clinically relevant nonmajor bleeding 80
in the group that received dual therapy with dabigatran 70

of Event (%)
at a dose of 110 mg versus the group that received tri- 60
ple therapy with warfarin (Panel A) and in the group 50
that received dual therapy with dabigatran at a dose of 40 Triple therapy
150 mg versus the corresponding triple-therapy group 30
(which did not include elderly patients outside the 20
10 Dual therapy (110 mg)
United States) (Panel B). Also shown is the incidence
0
of a secondary efficacy end point of a composite of 0 90 180 270 360 450 540 630 720
thromboembolic events (myocardial infarction, stroke,
Days to First Event
or systemic embolism), death, or unplanned revascu-
larization in the two dual-therapy groups combined No. at Risk
versus the triple-therapy group (Panel C). In Panel C, Dual therapy 981 898 834 671 538 384 258 162 86
(110 mg)
the inset shows the same data on an enlarged y axis. Triple therapy 981 800 719 580 453 302 205 124 63

B Primary End Point in Dual-Therapy Group (150 mg) vs. Triple-Therapy Group
therapy group than in the corresponding triple- 100
Hazard ratio, 0.72 (95% CI, 0.580.88)
therapy group (0.1% vs. 1.0%; hazard ratio, 0.12; 90 P<0.001 for noninferiority

Cumulative Incidence
80
95% CI, 0.02 to 0.98; P=0.047). 70

of Event (%)
60
Secondary Efficacy End Points 50
The incidence of the composite efficacy end 40 Corresponding triple therapy
30
point of thromboembolic events (myocardial 20 Dual therapy (150 mg)
infarction, stroke, or systemic embolism), death, 10
or unplanned revascularization was 13.7% in the 0
0 90 180 270 360 450 540 630 720
two dual-therapy groups combined as compared
Days to First Event
with 13.4% in the triple-therapy group (hazard
ratio, 1.04; 95% CI, 0.84 to 1.29; P=0.005 for No. at Risk
Dual therapy 763 694 640 514 404 278 182 113 65
noninferiority) (Table3). The incidence was (150 mg)
15.2% in the 110-mg dual-therapy group as com- Corresponding 764 630 562 446 349 222 152 88 47
triple therapy
pared with 13.4% in the triple-therapy group
(hazard ratio, 1.13; 95% CI, 0.90 to 1.43; P=0.30) C Secondary Efficacy End Point in Dual-Therapy Groups (Combined)
vs. Triple-Therapy Group
and 11.8% in the 150-mg dual-therapy group as
35
compared with 12.8% in the corresponding tri- Hazard ratio, 1.04 (95% CI, 0.841.29)
30 P=0.005 for noninferiority
ple-therapy group (hazard ratio, 0.89; 95% CI,
25 Dual therapy (combined)
0.67 to 1.19; P=0.44) (Fig. S3 in the Supplemen-
100 20
tary Appendix). Results of the intention-to-treat 90
analysis were consistent with results of the on- 15
Cumulative Incidence

80
Triple therapy
treatment analysis and with results across mul- 70 10
of Event (%)

60
tiple subgroups of patients, including those who 50
5
had an acute coronary syndrome and those who 40 0
0 90 180 270 360 450 540 630 720
had received a drug-eluting stent (Table S10 and 30
Fig. S5 in the Supplementary Appendix). The rate 20
10
of the combined end point of thromboembolic 0
events or death was 9.6% in the two dual-therapy 0 90 180 270 360 450 540 630 720
groups combined as compared with 8.5% in the Days to First Event
triple-therapy group (hazard ratio, 1.17; 95% CI, No. at Risk
0.90 to 1.53; P=0.11 for noninferiority). An over- Dual therapy 1744 1660 1561 1257 1003 720 481 295 161
(combined)
all summary of the hierarchical testing is shown Triple therapy 981 921 854 700 548 383 259 161 81
in Figure S4 in the Supplementary Appendix.

n engl j med 377;16nejm.org October 19, 2017 1519


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The n e w e ng l a n d j o u r na l of m e dic i n e

Rates of additional efficacy end points are

noninferiority)

P values for noninferiority were calculated at a one-sided alpha level of 0.025 and are provided only if a noninferiority margin was prespecified. All other P values are for superiority and
point were considered to be descriptive. Details about International Society on Thrombosis and Hemostasis (ISTH) bleeding categories are provided in Table S2 in the Supplementary
(<0.001 for
shown in Table3. The absolute number of patients

years of age in Japan]). Comparisons between the 150-mg dual-therapy group and the corresponding triple-therapy group were unstratified. All end points other than the primary end
P Value

<0.001
0.047

0.009

* Comparisons between the 110-mg dual-therapy group and the triple-therapy group were stratified according to age group (nonelderly or elderly [<80 or 80 years of age; <70 or 70
0.002

0.02

0.03
with definite stent thrombosis was low; events oc-
curred in 15 patients (1.5%) in the 110-mg dual-
therapy group as compared with 8 (0.8%) in the
0.72 (0.580.88) triple-therapy group (P=0.15) and in 7 patients

0.64 (0.430.94)
0.72 (0.610.84)
0.12 (0.020.98)
0.51 (0.280.93)
0.53 (0.330.85)
Hazard Ratio

(0.9%) in the 150-mg dual-therapy group as


(95% CI)

compared with 7 (0.9%) in the corresponding


triple-therapy group (P=0.98).

Serious Adverse Events


Corresponding
with Dabigatran, Triple Therapy
with Warfarin

Analyses of adverse events included patients who


196 (25.7)

316 (41.4)
(N=764)

64 (8.4)

8 (1.0)
30 (3.9)
48 (6.3) had received at least one dose of the trial antico-
agulant. Serious adverse events that occurred
during treatment were reported in 42.7% of the
no. (%)

patients in the 110-mg dual-therapy group, 39.6%


Dual Therapy

in the 150-mg dual-therapy group, and 41.8% in


154 (20.2)

254 (33.3)
(N=763)

43 (5.6)

1 (0.1)
16 (2.1)
27 (3.5)
150 mg

the triple-therapy group (Table S11 in the Supple-


mentary Appendix). Fatal serious adverse events
occurred during treatment in 38 patients (3.9%)
in the 110-mg dual-therapy group, 24 (3.2%) in
noninferiority)
(<0.001 for

the 150-mg dual-therapy group, and 41 (4.3%) in


P Value

<0.001

<0.001
<0.001

0.002
<0.001
0.06

the triple-therapy group. Details regarding the


most common serious adverse events and adverse
events that led to discontinuation of treatment are
shown in Tables S12 and S13 in the Supplemen-
0.52 (0.420.63)

0.52 (0.370.74)
0.54 (0.460.63)
0.30 (0.081.07)
0.37 (0.200.68)
0.41 (0.260.63)
Hazard Ratio

tary Appendix.
(95% CI)

Discussion
The RE-DUAL PCI trial showed that, among pa-
tients with atrial fibrillation who had undergone
Triple Therapy
with Warfarin

264 (26.9)

421 (42.9)
(N=981)

90 (9.2)

10 (1.0)
37 (3.8)
69 (7.0)

PCI, two different regimens of full-dose antico-


agulation therapy with dabigatran (either 110 mg
Appendix. TIMI denotes Thrombolysis in Myocardial Infarction.

or 150 mg twice daily) plus a P2Y12 inhibitor


no. (%)

(clopidogrel or ticagrelor) resulted in a risk of


with Dabigatran,

major or clinically relevant nonmajor bleeding


Dual Therapy

151 (15.4)

266 (27.1)
(N=981)

49 (5.0)

3 (0.3)
14 (1.4)
29 (3.0)

events that was significantly lower than the risk


110 mg

were calculated at a two-sided alpha level of 0.05.

with triple therapy with warfarin; in addition,


dual therapy with dabigatran was noninferior to
triple therapy with warfarin with respect to the
Primary end point: ISTH major or clin-

composite efficacy end point of thromboembolic


ically relevant nonmajor bleeding

events, death, or unplanned revascularization. For


the primary end point of major or clinically rele-
TIMI major or minor bleeding
Table 2. Safety End Points.*

vant nonmajor bleeding, the difference in risk


Intracranial hemorrhage

between the 110-mg dual-therapy group and the


ISTH major bleeding

TIMI major bleeding

triple-therapy group was 48% (11.5 percentage


points) and the difference in risk between the
Total bleeding

150-mg dual-therapy group and the correspond-


End Point

ing triple-therapy group was 28% (5.5 percentage


points) during approximately 1 year of treatment.
Rates of ISTH and TIMI major bleeding were sig-

1520 n engl j med 377;16nejm.org October 19, 2017

The New England Journal of Medicine


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Copyright 2017 Massachusetts Medical Society. All rights reserved.
Table 3. Efficacy End Points.*

Dual Therapy with Dabigatran (Combined) Dual Therapy with Dabigatran (110 mg) Dual Therapy with Dabigatran (150 mg)
End Point vs. Triple Therapy with Warfarin vs. Triple Therapy with Warfarin vs. Triple Therapy with Warfarin

Combined 110-mg 150-mg


Dual- Triple- Dual- Triple- Dual- Corresponding
Therapy Therapy Hazard Therapy Therapy Hazard Therapy Triple-Therapy Hazard
Groups Group Ratio P Group Group Ratio P Group Group Ratio P
(N=1744) (N=981) (95% CI) Value (N=981) (N=981) (95% CI) Value (N=763) (N=764) (95% CI) Value

no. (%) no. (%) no. (%)


Composite efficacy end point: 239 (13.7) 131 (13.4) 1.04 0.74 149 (15.2) 131 (13.4) 1.13 0.30 90 (11.8) 98 (12.8) 0.89 0.44
thromboembolic events, (0.841.29) (0.005 for (0.901.43) (0.671.19)
death, or unplanned revas- noninferiority)
cularization
Thromboembolic events or 168 (9.6) 83 (8.5) 1.17 0.25 108 (11.0) 83 (8.5) 1.30 0.07 60 (7.9) 60 (7.9) 0.97 0.88
death (0.901.53) (0.11 for (0.981.73) (0.681.39)
noninferiority)
Death 55 (5.6) 48 (4.9) 1.12 0.56 30 (3.9) 35 (4.6) 0.83 0.44
(0.761.65) (0.511.34)
Myocardial infarction 44 (4.5) 29 (3.0) 1.51 0.09 26 (3.4) 22 (2.9) 1.16 0.61
(0.942.41) (0.662.04)
Stroke 17 (1.7) 13 (1.3) 1.30 0.48 9 (1.2) 8 (1.0) 1.09 0.85
(0.632.67) (0.422.83)

The New England Journal of Medicine


n engl j med 377;16nejm.org October 19, 2017
Definite stent thrombosis 15 (1.5) 8 (0.8) 1.86 0.15 7 (0.9) 7 (0.9) 0.99 0.98
(0.794.40) (0.352.81)
Dual Antithrombotic Ther apy with Dabigatr an

* Thromboembolic events were myocardial infarction, stroke, or systemic embolism. Unplanned revascularization was percutaneous coronary intervention or coronary-artery bypass graft-
ing. Comparisons between the 110-mg dual-therapy group and the triple-therapy group and between the combined dual-therapy groups and the triple-therapy group were stratified ac-

Copyright 2017 Massachusetts Medical Society. All rights reserved.


cording to age group (nonelderly or elderly [<80 or 80 years of age; <70 or 70 years of age in Japan]). Comparisons between the 150-mg dual-therapy group and the corresponding tri-
ple-therapy group were unstratified. All end points other than the composite efficacy end point and the combined end point of thromboembolic events or death were considered to be
descriptive.
P values for noninferiority were calculated at a one-sided alpha level of 0.025 and are provided only if a noninferiority margin was prespecified. All other P values are for superiority and
were calculated at a two-sided alpha level of 0.05; these P values are provided for descriptive purposes only.

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1521
The n e w e ng l a n d j o u r na l of m e dic i n e

nificantly lower in both dual-therapy groups than Randomized, Controlled, Multicenter Study Ex-
in the triple-therapy group, findings that reaf- ploring Two Treatment Strategies of Rivaroxaban
firmed the safety of dabigatran in these regimens, and a Dose-Adjusted Oral Vitamin K Antagonist
even at a dose of 150 mg. In the 110-mg dual-ther- Treatment Strategy in Subjects with Atrial Fibril-
apy group, the rate of major bleeding was sig- lation who Undergo Percutaneous Coronary In-
nificantly lower (by 4.2 percentage points) and tervention) showed that the rates of clinically
the rate of major thromboembolic events was significant bleeding associated with dual therapy
nonsignificantly higher (by 1.8 percentage points) with three-quarter-dose rivaroxaban, as well as
than the rates in the triple-therapy group, find- the rates associated with triple therapy with very-
ings that suggest a balance of the risk of bleed- low-dose rivaroxaban, were lower than the rates
ing with the prevention of thromboembolism. In with triple therapy with warfarin.20 The doses of
the 150-mg dual-therapy group, the rate of major rivaroxaban that were used in the PIONEER AF-PCI
bleeding was significantly lower (by 2.8 percent- trial were lower than the dose used for stroke
age points) and the rate of major thromboembolic prevention in the ROCKET-AF trial (Rivaroxaban
events was nonsignificantly lower (by 1.0 percent- Once Daily Oral Direct Factor Xa Inhibition
age point) than the rates in the corresponding tri- Compared with Vitamin K Antagonism for Pre-
ple-therapy group. These findings indicate a net vention of Stroke and Embolism Trial in Atrial
clinical benefit of each of the two dual-therapy Fibrillation).29
regimens, and clinicians could potentially select With respect to the composite efficacy end
one of these two regimens on the basis of a pa- point, our prespecified criterion for noninferior-
tients risk of bleeding and risk of thromboem- ity was met. This trial, which involved 2725 pa-
bolic events. tients, was not powered to allow for compari-
The strategies for dual therapy with dabigatran sons of individual components of this end point.
that we tested incorporated two changes relative We thus have to exercise caution in examining
to the previous standard of care (triple therapy with the nonsignificant small numerical excesses in
warfarin). First, we evaluated two doses of dabiga- some components of this end point. It is impor-
tran, each of which has been approved worldwide tant to note that we studied dabigatran doses that
for stroke prevention and has been shown to be have previously been shown (in the RE-LY trial,16
safe and efficacious.16 The benefits with respect to which involved 18,000 patients) to each provide
lower rates of bleeding parallel those seen previ- stroke prevention in patients with atrial fibrilla-
ously in the RE-LY trial (Randomized Evaluation tion. In choosing any antithrombotic regimen, it
of Long-Term Anticoagulant Therapy)16 but ap- is necessary to balance the risk of bleeding with
pear to be amplified in this population of pa- prevention of thromboembolic events. During
tients, who had a particularly high risk of bleed- recent years, clinical guidelines4 and consensus
ing and in whom aspirin was discontinued after statements1,3 have evolved and now suggest that
PCI, at the time of randomization. As such, the dual antithrombotic therapy is an option in this
RE-DUAL PCI trial is a large randomized trial patient population (class IIb recommendation).
that validates the concept put forth in the WOEST Our findings in evaluating two regimens of dual
trial (What is the Optimal Antiplatelet and Anti- therapy with dabigatran provide evidence that
coagulant Therapy in Patients with Oral Antico- supports these changes in the guidelines for the
agulation and Coronary Stenting),18 but with great- treatment of this patient population.
er statistical power. There are limitations to our trial. First, we
In the group that received triple therapy with amended the protocol and enrolled a smaller num-
warfarin, the duration of aspirin therapy was just ber of patients than we had originally planned to
1 to 3 months; we adopted this approach in ac- enroll, and this limits the power of the trial to
cordance with evolutions in practice and guide- examine efficacy according to dabigatran dose. For
lines.27,28 In effect, triple therapy shifted to dual the comparison of the composite efficacy end
therapy for most of the trial period; despite this point, we combined the dual-therapy groups,
factor, we found that the risk of bleeding was ap- which gave the analysis reasonable power (83.6%),
proximately one half and one quarter lower in the and we prespecified that the comparison was
110-mg and 150-mg dual-therapy groups, respec- part of formal hierarchical testing. Second, al-
tively, than in the triple-therapy group. The re- though our noninferiority boundary was based
sults of the PIONEER AF-PCI trial (Open-Label, on previous studies of atrial fibrillation, it was

1522 n engl j med 377;16nejm.org October 19, 2017

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Dual Antithrombotic Ther apy with Dabigatr an

used for a different end point. Finally, with re- participating in an unfunded research collaboration with FlowCo,
PLx Pharma, Takeda, and Merck; Dr. Oldgren, receiving lecture
spect to the results for both the bleeding and
fees and consulting fees, paid to his institution, from Bayer,
thromboembolic-event end points, we may only Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, and Sanofi; Dr. Lip,
speculate on the relative contributions of the receiving lecture fees from Bayer and Roche, consulting fees
omission of aspirin and the type of oral antico- from BayerJanssen and Biotronik, and lecture fees and consult-
ing fees from Bristol-Myers SquibbPfizer, Medtronic, Boehringer
agulant in the dual-therapy groups and the tri- Ingelheim, Microlife, and Daiichi Sankyo; Dr. Mng, receiving
ple-therapy group. A trial conducted with a formal advisory board fees from Bayer and AstraZeneca; Dr. Merkely,
2-by-2 factorial design would be able to discern receiving grant support from Boston Scientific and Biotronik,
and lecture fees from Medtronic and Terumo; Dr. Zeymer, receiv-
these contributions, and one such trial is ongoing ing lecture fees from Novartis and Sanofi, lecture fees and con-
(ClinicalTrials.gov number, NCT02415400). sulting fees from The Medicines Company and Amgen, and grant
In summary, we found that, among patients support, lecture fees, and consulting fees from AstraZeneca; Dr.
Gropper, Dr. Nordaby, Ms. Kleine, Dr. Harper, and Ms. Manassie,
with atrial fibrillation who had undergone PCI, being employed by Boehringer Ingelheim; Dr. Januzzi, receiving
dual therapy with dabigatran and a P2Y12 inhibi- grant support and consulting fees from Roche, grant support
tor resulted in a risk of bleeding events that was from Prevencio, Siemens, and Singulex, fees for serving on data
and safety monitoring boards for Amgen, grant support and
significantly lower than the risk with triple ther- fees for serving on a clinical end-point adjudication committee
apy with warfarin, a P2Y12 inhibitor, and aspirin; for Novartis, consulting fees and fees for serving on a clinical
in addition, dual therapy with dabigatran was end-point adjudication committee for Janssen, fees for serving on
clinical end-point adjudication committees for Pfizer, AbbVie,
noninferior to triple therapy with warfarin with and Bayer; Dr. ten Berg, receiving grant support, advisory board
respect to the rate of thromboembolic events. In fees, consulting fees, and lecture fees from AstraZeneca, advi-
the dual-therapy regimens, each of the two doses sory board fees, consulting fees, and lectures fees from Eli Lilly,
Daiichi Sankyo, The Medicines Company, Accumetrics, Boeh-
of dabigatran led to a balance between the risk ringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Bayer, and
of bleeding and the prevention of thromboem- grant support from ZonMw; Dr. Steg, receiving fees for serving
bolic events, which offers clinicians two additional on a steering committee from Amarin, Janssen, and CSL Behring,
fees for serving on a steering committee and lecture fees from
options for the treatment of patients with varying
AstraZeneca, lecture fees and consulting fees from Bayer and
risks of thromboembolic events and bleeding. Bristol-Myers Squibb, fees for preparation of educational mate-
Supported by Boehringer Ingelheim. rial from Boehringer Ingelheim, consulting fees and fees for
Dr. Cannon reports receiving research support and consulting serving on a data and safety monitoring board from Lilly and
fees from Arisaph Pharmaceuticals, Takeda Pharmaceuticals, Merck Sharpe & Dohme, consulting fees from Novartis and Re-
Bristol-Myers Squibb, Amgen, and Merck, research support from generon, fees for serving on a critical event committee from
Janssen and Daiichi Sankyo, and consulting fees from LipimetiX, Pfizer, grant support, fees for serving on a steering committee,
Pfizer, Sanofi, Regeneron, Kowa, Alnylam, Amarin, GlaxoSmith and consulting fees from Sanofi, and grant support, fees for serv-
Kline, AstraZeneca, and Eisai; Dr. Bhatt, receiving research ing on a steering committee, consulting fees, and fees for serving
support from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, on a data and safety monitoring board from Servier; and Dr.
Ethicon, Medtronic, Sanofi-Aventis, The Medicines Company, Hohnloser, receiving consulting fees and fees for serving on a
Roche, Pfizer, Forest LaboratoriesAstraZeneca, Ischemix, Amgen, speaker bureau from Boehringer Ingelheim, Bayer Healthcare,
Lilly, Chiesi, and Ironwood Pharmaceuticals, fees for serving on Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Medtronic, and Zoll.
data and safety monitoring committees and a clinical trial steer- No other potential conflict of interest relevant to this article was
ing committee from Population Health Research Institute, advi- reported.
sory board fees from Elsevier, Medscape Cardiology, Regado Disclosure forms provided by the authors are available with
Biosciences, and Cardax, fees for serving on CME steering com- the full text of this article at NEJM.org.
mittees from WebMD, fees for serving as site co-investigator for We thank Priscilla Driscoll Shempp, M.B.A., and Joseph M.
Biotronik and Boston Scientific, fees for serving on data and Massaro, Ph.D., from the Baim Institute for Clinical Research
safety monitoring committees from Icahn School of Medicine at for their contributions; and Dr. Martina Brckmann, Monika
Mount Sinai, and fees for serving in various editorial roles (editor- Simetzberger, Jens Laass, Kevin Devenny, Jon Blatchford, Her-
in-chief of the Harvard Heart Letter for Belvoir Publications, chief bert Noack, Sufian Chowdhury, Claudia Neumann, James Lee,
medical editor of Cardiology Todays Intervention for Slack Publica- Pol Mac an Mhoir, Lee Polley, Elly Carroll, and Avril Parkes from
tions, editor-in-chief of the Journal of Invasive Cardiology from HMP Boehringer Ingelheim for their contributions over the years,
Communications, and deputy editor of Clinical Cardiology), and which were key to the development and conduct of the trial.

Appendix
The authors affiliations are as follows: the Baim Institute for Clinical Research (C.P.C., J.L.J.), Brigham and Womens Hospital, Heart
and Vascular Center, and Harvard Medical School (C.P.C., D.L.B.), and the Cardiology Division, Massachusetts General Hospital, and
Harvard Medical School (J.L.J.) all in Boston; Uppsala Clinical Research Center and Department of Medical Sciences, Uppsala Uni-
versity, Uppsala, Sweden (J.O.); the Institute of Cardiovascular Sciences, University of Birmingham, Birmingham (G.Y.H.L.), Boeh-
ringer Ingelheim, Bracknell (R.H., J.M.), and Imperial College, London, London (P.G.S.) all in the United Kingdom; Cleveland
Clinic, Cleveland (S.G.E.); Kyoto University, Department of Cardiovascular Medicine, Kyoto, Japan (T.K.); Aarhus University Hospital,
Skejby, Denmark (M.M.); University Heart and Vascular Center, Budapest, Hungary (B.M.); Klinikum der Stadt Ludwigshafen am
Rhein, Medizinische Klinik B, Ludwigshafen (U.Z.), Boehringer Ingelheim, Ingelheim (S.G., M.N., E.K.), and Johann Wolfgang Goethe
University, Department of Medicine, Division of Cardiology, Frankfurt am Main (S.H.H.) all in Germany; St. Antonius Ziekenhuis,
Nieuwegein, the Netherlands (J.M.B.); and the French Alliance for Cardiovascular Trials, F-CRIN Network, DHU FIRE, Universit Paris
Diderot, INSERM Unit 1148, and Hpital Bichat Assistance Publique, Paris (P.G.S.).

n engl j med 377;16nejm.org October 19, 2017 1523


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Dual Antithrombotic Ther apy with Dabigatr an

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